A NIR-Ⅱ-Immunostimulatory nanoplatform rewires immunometabolism to unleash STING-driven antitumor immunity

Background: Melanoma represents a highly aggressive and immunotherapy-resistant malignancy with limited immunotherapy efficacy, underscoring the urgent need for novel treatment strategies that integrate precise diagnosis and potent immunomodulation. The combination of photothermal therapy (PTT) and STING pathway activation has emerged as a promising approach to potentiate antitumor immunity. Nevertheless, it remains challenging to integrate real-time deep-tissue imaging with spatiotemporally synchronized immunostimulation within a single nanoplatform, especially for the effective treatment of advanced melanoma.

Results: Herein, we report a mitochondria-targeted nanotheranostic agent (IRM) constructed through molecular co-assembly of a STING agonist (MSA-2) and a lab-synthesized NIR-Ⅱ fluorophore (IR-817). This nanoplatform enables simultaneous NIR-Ⅱ fluorescence imaging and high-efficiency photothermal conversion (η = 52.79%). More importantly, it ensures efficient, on-demand drug action through spatiotemporally controlled delivery. Under 808 nm laser irradiation, IRM induced localized hyperthermia that provoked Pyroptosis and immunogenic cell death (ICD) in primary melanoma tumors. Concurrently, the photothermal stimulus promoted the rapid release of MSA-2, which synergistically activated the STING pathway in dendritic cells (DCs). This event drove immunometabolic reprogramming of the tumor microenvironment, elicited a robust systemic cytotoxic T-cell response, and effectively reversed the immunosuppressive state. This cascade of biological events ultimately led to significant inhibition of distant tumors, demonstrating a robust abscopal effect. Crucially, this therapeutic effect was strictly STING-dependent: in STING-KO mouse models, the suppression of distant tumors was completely abolished following the same treatment. These complementary experimental outcomes directly confirm the indispensable synergy between PTT and STING pathway activation, which together constitute the core mechanism underlying the induction of systemic antitumor immunity by the IRM nanoplatform.

Conclusions: Our study illustrates that the IRM nanoplatform effectively merges multimodal imaging with immunometabolic modulation, establishing a durable and systemic antitumor immunity. This work offers a translatable strategy for combinational photo-immunotherapy against advanced melanoma.

Immunometabolic reprogramming; NIR-Ⅱ imaging; Photothermal therapy; Pyroptosis; STING pathway.